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Endocrine

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Thyroid profile during the alternative Sunitinib dosing 2/1 schedule in metastatic renal cell carcinoma

  • L. Rizza
  • E. Sbardella
  • D. Gianfrilli
  • R. Lauretta
  • M. Tenuta
  • G. Del Bene
  • F. Longo
  • A. Faggiano
  • A. Lenzi
  • E. Giannetta
  • C. PozzaEmail author
Original Article
  • 30 Downloads

Abstract

Purpose

Hypothyroidism is a common side effect of Sunitinib (SUN) treatment in metastatic renal cell carcinoma (mRCC) patients. We aimed to evaluate thyroid profile during the alternative 2/1 SUN treatment schedule and to assess the predictive value of hypothyroidism in terms of survival.

Methods

We performed a prospective observational study enrolling 42 consecutive mRCC patients starting first-line alternative SUN dosing 2/1 schedule. Thyroid function was assessed at baseline and during the first three SUN cycles (1 cycle = 6 weeks = 2 ON/1 OFF + 2 ON/1 OFF), and then after 6 and 12 months. Thyroid ultrasound was performed at baseline and after 3, 6, and 12 months.

Results

Subclinical hypothyroidism developed in 24% of patients during the first cycle; in other 24% in the second cycle and in 14% in the third cycle. The highest TSH values were reached during the second cycle, ON phase (6.58 ± 5.74 μI U/l). We observed a reduction in thyroid size, in echogenicity and in parenchymal perfusion in all patients. Progression-free survival (PFS) tended to be longer in patients with TSH ≥ 5 μI U/ml during the second cycle (p = 0.069). TSH level was an independent risk factor for PFS in men (p = 0.009) but not in women (p = 0.285).

Conclusions

This is the first study investigating functional and morphological effects on thyroid during the alternative 2/1 SUN schedule in mRCC patients. We detected an early onset of subclinical hypothyroidism, observing the association between TSH ≥ 5 μI U/ml and: (i) longer PFS in men; (ii) progressive decrease of thyroid size in absence of significant changes in autoimmune thyroid profile.

Keywords

Tyrosine kinase inhibitors Hypothyroidism TSH Target therapy 

Abbreviations

RCC

renal cell carcinoma

mRCC

metastatic renal cell carcinoma

IL-2

interleukin-2

IFN-α

interferon-α

VHL

von Hippel Lindau

VEGF

vascular endothelial growth factor

PDGF

platelet-derived growth factor

VEGFR

vascular endothelial growth factor receptor

PDGFR

platelet-derived growth factor receptor

TKIs

tyrosine kinase inhibitors

SUN

Sunitinib

ATP

adenosine triphosphate

PFS

progression free survival

ORR

overall response rate

OS

overall survival

FFS

free survival rate

TTP

time to progression

CTC

common toxicity criteria

TSH

thyroid stimulating hormone

FT4

free thyroxine

T3

triiodothyronine

FT3

free triiodothyronine

TPO

thyroid peroxidase

TGAb

anti-thyroglobulin antibody

TPOAb

anti-thyroid peroxidase antibody

FSH

follicle stimulating hormone

D3

type III deiodinase

RECIST

response evaluation criteria in solid tumors

OLS

ordinary least squares

LT

levothyroxine

Notes

Authors contributions

L.R., C.P., E.S., and E.G. designed and coordinated the study. F.L. and G.D.B. enrolled and followed patients. L.R., E.S., D.G., R.L., and M.T. followed and managed endocrine aspects of patients and performed US images. C.P., E.G., and A.F. performed quality control checks and separately analyzed thyroid US images. C.P. performed statistical analysis of the data. A.L. verified the analytic method. L.R., E.S., E.G., C.P., and A.F. contributed to the final version of the manuscript.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the iwenstitutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

References

  1. 1.
    D.B. Mendel, A.D. Laird, X. Xin, S.G. Louie, J.G. Christensen, G. Li, R.E. Schreck, T.J. Abrams, T.J. Ngai, L.B. Lee, L.J. Murray, J. Carver, E. Chan, K.G. Moss, J.O. Haznedar, J. Sukbuntherng, R.A. Blake, L. Sun, C. Tang, T. Miller, S. Shirazian, G. McMahon, J.M. Cherrington, In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327–337 (2003)Google Scholar
  2. 2.
    G.D. Demetri, P. Reichardt, Y.K. Kang, J.Y. Blay, P. Rutkowski, H. Gelderblom, P. Hohenberger, M. Leahy, M. von Mehren, H. Joensuu, G. Badalamenti, M. Blackstein, A. Le Cesne, P. Schoffski, R.G. Maki, S. Bauer, B.B. Nguyen, J. Xu, T. Nishida, J. Chung, C. Kappeler, I. Kuss, D. Laurent, P.G. Casali; investigators Gs, Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 295–302 (2013)PubMedCrossRefGoogle Scholar
  3. 3.
    R.J. Motzer, T.E. Hutson, P. Tomczak, M.D. Michaelson, R.M. Bukowski, S. Oudard, S. Negrier, C. Szczylik, R. Pili, G.A. Bjarnason, X. Garcia-del-Muro, J.A. Sosman, E. Solska, G. Wilding, J.A. Thompson, S.T. Kim, I. Chen, X. Huang, R.A. Figlin, Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 27, 3584–3590 (2009)PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    E. Raymond, L. Dahan, J.L. Raoul, Y.J. Bang, I. Borbath, C. Lombard-Bohas, J. Valle, P. Metrakos, D. Smith, A. Vinik, J.S. Chen, D. Horsch, P. Hammel, B. Wiedenmann, E. Van Cutsem, S. Patyna, D.R. Lu, C. Blanckmeister, R. Chao, P. Ruszniewski, Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New Engl. J. Med. 364, 501–513 (2011)PubMedCrossRefGoogle Scholar
  5. 5.
    N.K. Janzen, H.L. Kim, R.A. Figlin, A.S. Belldegrun, Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urologic Clin. N Am. 30, 843–852 (2003)CrossRefGoogle Scholar
  6. 6.
    B.E. Houk, C.L. Bello, B. Poland, L.S. Rosen, G.D. Demetri, R.J. Motzer, Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother. Pharmacol. 66, 357–371 (2010)PubMedCrossRefGoogle Scholar
  7. 7.
    M.E. Gore, C. Szczylik, C. Porta, S. Bracarda, G.A. Bjarnason, S. Oudard, S.H. Lee, J. Haanen, D. Castellano, E. Vrdoljak, P. Schoffski, P. Mainwaring, R.E. Hawkins, L. Crino, T.M. Kim, G. Carteni, W.E. Eberhardt, K. Zhang, K. Fly, E. Matczak, M.J. Lechuga, S. Hariharan, R. Bukowski, Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma. Br. J. Cancer 113, 12–19 (2015)PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    R.J. Motzer, T.E. Hutson, D. Cella, J. Reeves, R. Hawkins, J. Guo, P. Nathan, M. Staehler, P. de Souza, J.R. Merchan, E. Boleti, K. Fife, J. Jin, R. Jones, H. Uemura, U. De Giorgi, U. Harmenberg, J. Wang, C.N. Sternberg, K. Deen, L. McCann, M.D. Hackshaw, R. Crescenzo, L.N. Pandite, T.K. Choueiri, Pazopanib versus sunitinib in metastatic renal-cell carcinoma. New Engl. J. Med. 369, 722–731 (2013)PubMedCrossRefGoogle Scholar
  9. 9.
    J.L. Lee, M.K. Kim, I. Park, J.H. Ahn, D.H. Lee, H.M. Ryoo, C. Song, B. Hong, J.H. Hong, H. Ahn, Randomized phase II trial of Sunitinib four weeks on and two weeks off versus two weeks on and one week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial. Ann. Oncol. 26, 2300–2305 (2015)PubMedCrossRefGoogle Scholar
  10. 10.
    H. Miyake, K. Harada, A. Miyazaki, M. Fujisawa, Improved health-related quality of life of patients with metastatic renal cell carcinoma treated with a 2 weeks on and 1 week off schedule of sunitinib. Med. Oncol. 32, 78 (2015)PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    X. Zhang, G. Sun, J. Zhao, K. Shu, P. Zhao, J. Liu, Y. Yang, Q. Tang, J. Chen, P. Shen, J. Wang, H. Zeng, Improved long-term clinical outcomes and safety profile of sunitinib dosing schedule with 4/2 switched to 2/1 in patients with metastatic renal cell carcinoma. J. Cancer 9, 3303–3310 (2018)PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    G. Di Lorenzo, C. Porta, J. Bellmunt, C. Sternberg, Z. Kirkali, M. Staehler, S. Joniau, F. Montorsi, C. Buonerba, Toxicities of targeted therapy and their management in kidney cancer. Eur. Urol. 59, 526–540 (2011)PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    H. Miyake, T. Kurahashi, K. Yamanaka, Y. Kondo, M. Muramaki, A. Takenaka, T.A. Inoue, M. Fujisawa, Abnormalities of thyroid function in Japanese patients with metastatic renal cell carcinoma treated with sorafenib: a prospective evaluation. Urologic Oncol. 28, 515–519 (2010)CrossRefGoogle Scholar
  14. 14.
    B.I. Rini, I. Tamaskar, P. Shaheen, R. Salas, J. Garcia, L. Wood, S. Reddy, R. Dreicer, R.M. Bukowski, Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J. Natl. Cancer Inst. 99, 81–83 (2007)PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    E. Wong, L.S. Rosen, M. Mulay, A. Vanvugt, M. Dinolfo, C. Tomoda, M. Sugawara, J.M. Hershman, Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 17, 351–355 (2007)PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    V. Baldazzi, R. Tassi, A. Lapini, C. Santomaggio, M. Carini, R. Mazzanti, The impact of sunitinib-induced hypothyroidism on progression-free survival of metastatic renal cancer patients: a prospective single-center study. Urologic Oncol. 30, 704–710 (2012)CrossRefGoogle Scholar
  17. 17.
    J. Desai, L. Yassa, E. Marqusee, S. George, M.C. Frates, M.H. Chen, J.A. Morgan, S.S. Dychter, P.R. Larsen, G.D. Demetri, E.K. Alexander, Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann. Intern. Med. 145, 660–664 (2006)PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    D. Mannavola, P. Coco, G. Vannucchi, R. Bertuelli, M. Carletto, P.G. Casali, P. Beck-Peccoz, L. Fugazzola, A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J. Clin. Endocrinol. Metab. 92, 3531–3534 (2007)PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    L.M. Riesenbeck, S. Bierer, I. Hoffmeister, T. Kopke, P. Papavassilis, L. Hertle, B. Thielen, E. Herrmann, Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J. Urol. 29, 807–813 (2011)PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    R. Sabatier, J.C. Eymard, J. Walz, J.L. Deville, H. Narbonne, J.M. Boher, N. Salem, M. Marcy, S. Brunelle, P. Viens, F. Bladou, G. Gravis, Could thyroid dysfunction influence outcome in sunitinib-treated metastatic renal cell carcinoma? Annals of oncology: official journal of the European Society for. Med. Oncol. 23, 714–721 (2012)Google Scholar
  21. 21.
    M. Schmidinger, U.M. Vogl, M. Bojic, W. Lamm, H. Heinzl, A. Haitel, M. Clodi, G. Kramer, C.C. Zielinski, Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 117, 534–544 (2011)PubMedCrossRefGoogle Scholar
  22. 22.
    N. Shinohara, M. Takahashi, T. Kamishima, H. Ikushima, N. Otsuka, A. Ishizu, C. Shimizu, H. Kanayama, K. Nonomura, The incidence and mechanism of sunitinib-induced thyroid atrophy in patients with metastatic renal cell carcinoma. Br. J. Cancer 104, 241–247 (2011)PubMedCrossRefGoogle Scholar
  23. 23.
    P. Wolter, C. Stefan, B. Decallonne, H. Dumez, M. Bex, P. Carmeliet, P. Schoffski, The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br. J. Cancer 99, 448–454 (2008)PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    O. Bozkurt, H. Karaca, I. Hacibekiroglu, M.A. Kaplan, Y. Duzkopru, M. Uysal, V. Berk, M. Inanc, A.O. Duran, E. Ozaslan, M. Ucar, M. Ozkan, Is sunitinib-induced hypothyroidism a predictive clinical marker for better response in metastatic renal cell carcinoma patients? J. Chemother. 28, 230–234 (2016)PubMedCrossRefGoogle Scholar
  25. 25.
    V. Fatourechi, Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin. Proc. 84, 65–71 (2009)PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    M.I. Surks, E. Ortiz, G.H. Daniels, C.T. Sawin, N.F. Col, R.H. Cobin, J.A. Franklyn, J.M. Hershman, K.D. Burman, M.A. Denke, C. Gorman, R.S. Cooper, N.J. Weissman, Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. J. Am. Med. Assoc. 291, 228–238 (2004)CrossRefGoogle Scholar
  27. 27.
    D.S. Cooper, B. Biondi, Subclinical thyroid disease. Lancet 379, 1142–1154 (2012)CrossRefGoogle Scholar
  28. 28.
    F. Pani, F. Atzori, G. Baghino, F. Boi, L. Tanca, M.T. Ionta, S. Mariotti, Thyroid dysfunction in patients with metastatic carcinoma treated with Sunitinib: is thyroid autoimmunity involved? Thyroid 25, 1255–1261 (2015)PubMedCrossRefGoogle Scholar
  29. 29.
    J. Brunn, U. Block, G. Ruf, I. Bos, W.P. Kunze, P.C. Scriba, [Volumetric analysis of thyroid lobes by real-time ultrasound (author’s transl)]. Dtsch. Med. Wochenschr. 106, 1338–1340 (1981)PubMedCrossRefGoogle Scholar
  30. 30.
    A.M. Isidori, V. Cantisani, E. Giannetta, D. Diacinti, E. David, V. Forte, D. Elia, C. De Vito, E. Sbardella, D. Gianfrilli, F. Monteleone, J. Pepe, S. Minisola, G. Ascenti, V. D’Andrea, C. Catalano, F. D’Ambrosio, Multiparametric ultrasonography and ultrasound elastography in the differentiation of parathyroid lesions from ectopic thyroid lesions or lymphadenopathies. Endocrine 57, 335–343 (2017)PubMedCrossRefGoogle Scholar
  31. 31.
    S.W. Greenhouse, S. Geisser, On methods in the analysis of profile data. Psychometrika 24, 95–112 (1959)CrossRefGoogle Scholar
  32. 32.
    E.G. Grant, F.N. Tessler, J.K. Hoang, J.E. Langer, M.D. Beland, L.L. Berland, J.J. Cronan, T.S. Desser, M.C. Frates, U.M. Hamper, W.D. Middleton, C.C. Reading, L.M. Scoutt, A.T. Stavros, S.A. Teefey, Thyroid ultrasound reporting lexicon: white paper of the ACR Thyroid Imaging, Reporting and Data System (TIRADS) committee. J. Am. Coll. Radiol. 12, 1272–1279 (2015)PubMedCrossRefGoogle Scholar
  33. 33.
    M.L. Vetter, S. Kaul, N. Iqbal, Tyrosine kinase inhibitors and the thyroid as both an unintended and an intended target. Endocr. Pract. 14, 618–624 (2008)PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    S. Faivre, C. Delbaldo, K. Vera, C. Robert, S. Lozahic, N. Lassau, C. Bello, S. Deprimo, N. Brega, G. Massimini, J.P. Armand, P. Scigalla, E. Raymond, Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J. Clin. Oncol. 24, 25–35 (2006)PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    T. Kondo, T. Takagi, H. Kobayashi, J. Iizuka, T. Nozaki, Y. Hashimoto, E. Ikezawa, K. Yoshida, K. Omae, K. Tanabe, Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma–comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off. Jpn. J. Clin. Oncol. 44, 270–277 (2014)PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Y.G. Najjar, K. Mittal, P. Elson, L. Wood, J.A. Garcia, R. Dreicer, B.I. Rini, A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur. J. Cancer 50, 1084–1089 (2014)PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    S. Bracarda, R. Iacovelli, L. Boni, M. Rizzo, L. Derosa, M. Rossi, L. Galli, G. Procopio, M. Sisani, F. Longo, M. Santoni, F. Morelli, G. Di Lorenzo, A. Altavilla, C. Porta, A. Camerini, B. Escudier, G. Rainbow, Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann. Oncol. 26, 2107–2113 (2015)PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    F. Baffert, T. Le, B. Sennino, G. Thurston, C.J. Kuo, D. Hu-Lowe, D.M. McDonald, Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am. J. Physiol. Heart Circulatory Physiol. 290, H547–H559 (2006)CrossRefGoogle Scholar
  39. 39.
    F. Pani, F. Atzori, G. Baghino, F. Boi, M.T. Ionta, L. Tanca, M. Scartozzi, S. Mariotti, Hypothyroidism and thyroid autoimmunity as a prognostic biomarker of better response in metastatic cancer long-term survivors treated with Sunitinib. Thyroid 26, 1336–1337 (2016)PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    N. Makita, M. Miyakawa, T. Fujita, T. Iiri, Sunitinib induces hypothyroidism with a markedly reduced vascularity. Thyroid 20, 323–326 (2010)PubMedCrossRefGoogle Scholar
  41. 41.
    A. Rogiers, P. Wolter, K. Op de Beeck, M. Thijs, B. Decallonne, P. Schoffski, Shrinkage of thyroid volume in sunitinib-treated patients with renal-cell carcinoma: a potential marker of irreversible thyroid dysfunction? Thyroid 20, 317–322 (2010)PubMedCrossRefGoogle Scholar
  42. 42.
    Z. Javed, T. Sathyapalan, Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Therapeutic Adv. Endocrinol. Metab. 7, 12–23 (2016)CrossRefGoogle Scholar
  43. 43.
    S.H. Pearce, G. Brabant, L.H. Duntas, F. Monzani, R.P. Peeters, S. Razvi, J.L. Wemeau, 2013 ETA guideline: management of subclinical hypothyroidism. Eur. Thyroid J. 2, 215–228 (2013)PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    M.G. Lechner, C.M. Vyas, O.R. Hamnvik, E.K. Alexander, P.R. Larsen, T.K. Choueiri, T.E. Angell, Hypothyroidism during tyrosine kinase inhibitor therapy is associated with longer survival in patients with advanced nonthyroidal cancers. Thyroid 28, 445–453 (2018)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • L. Rizza
    • 1
  • E. Sbardella
    • 2
  • D. Gianfrilli
    • 2
  • R. Lauretta
    • 3
  • M. Tenuta
    • 2
  • G. Del Bene
    • 4
  • F. Longo
    • 4
  • A. Faggiano
    • 2
  • A. Lenzi
    • 2
  • E. Giannetta
    • 2
  • C. Pozza
    • 2
    Email author
  1. 1.Endocrinology Unit, Department of Oncology and Medical SpecialitiesAO San Camillo-ForlaniniRomeItaly
  2. 2.Department of Experimental MedicineSapienza University of RomeRomeItaly
  3. 3.Internal MedicineAngiolini Hospital of Bagno di RomagnaForlì CesenaItaly
  4. 4.Department of Radiological, Oncological and Anatomopathological SciencesSapienza University of RomeRomeItaly

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